The present invention relates to drug delivery and, more particularly, to a method and device for improving efficiency of convection-enhanced drug delivery.
In the area of drug delivery into the central nervous system (CNS), in particular for the treatment of neurological diseases, there have been extensive efforts for devising methods for delivering therapeutic agents into the desired neurological site. Peripheral administration of therapeutic agents for the treatment of CNS pathologies is mostly inefficient due to poor penetration of most drugs across the blood brain barrier (BBB). Direct drug delivery methods, such as direct injection, intracavitary instillation, intracavitary topical application, chronic low-flow microinfusion and controlled release from polymer implants, are restricted by the poor diffusion of drug through the tissue. Therefore, these drug delivery methods are only useful for treating a small volume of tissue surrounding the drug source.
Generally, diffusion of a compound in a tissue depends on the free concentration gradient and the diffusivity of the compound in the tissue. The diffusion in the tissue is slow for high molecular weight compounds, and higher for low molecular weight compounds. For the latter, however, capillary forces and oftentimes metabolism generally limit the diffusion efficiency and therapeutic drug levels can be obtained only close (a few millimeters) to the source of drug.
U.S. Pat. No. 5,720,720, the contents of which are hereby incorporated by reference, discloses a drug delivery technique known in the literature as “Convection-Enhanced Drug Delivery” and abbreviated to CED or CEDD. In this technique drugs delivery into the brain tumor is effected by application of pressure gradients (as opposed to concentration gradient). Specifically, CED involves positioning the tip of an infusion catheter within the brain tissue and supplying the drug through the catheter while maintaining a positive pressure gradient from the tip of the catheter during infusion. The catheter is connected to a pump which delivers the drug and maintains the desired pressure gradient throughout delivery of the drug. Drug delivery rates are typically about 0.5 to about 4.0 mcl/min with infusion distances of order of centimeters. This method is particularly useful for the delivery of drugs to solid nervous tissue.
In CED, fluid convection (bulk flow) in tissues occurs as a result of pressure gradients. Bulk flow of brain interstitial fluid occurs under normal conditions [Rosenberg G A, Kyner W T and Estrada E, “Bulk flow of brain interstitial fluid under normal and hyperosmolar conditions”, Am. J. Physiol., 238:F42-F49, 1980], with vasogenic edema [Reulen H J, Graham R, Spatz M and Klatzo I “role of pressure gradients and bulk flow in dynamics of vasogenic brain edema”, J. Neurosurg., 46:24-35, 1977] and after infusion of solutions directly into the brain parenchyma [Ohata K, Marmarou A, “Clearance of brain edema and macromolecules through the cortical extracellular space”, J. Neurosurg., 77:387-396, 1992]. CED supplements diffusion and greatly enhances the distribution of small and large molecules in the brain [Bobo et al., “Convection-enhanced delivery of macromolecules in the brain,” Proc. Natl. Asad. Sci. U.S.A., 91:2076-2080, 1994; Lieberman et al., “Convection-enhanced distribution of large molecules in gray matter during interstitial drug infusion”, J. Neurosurg., 82:1021-1029, 1995].
CED is capable of obtaining in situ drug concentrations several orders of magnitude greater than those achieved by systemic administration. The concentration profile is relatively flat up to the flow front, providing control over undesired toxicity [Paul. F. Morrison, Douglas W Laske, Hunt Bobo. High-flow microinfusion: tissue penetration and pharmacodynamics. Am. J. Physiol. 266: 292-305, 1994].
In a phase II clinical trial in which patients were treated with CED of Tf-CRM107 (a conjugate protein of diphtheria toxin with a point mutation linked by a thioester bond to human transferrin) a significant antitumor response rate of 35% was reported [M. Weaver and D W Laske, “Transferrin receptor ligand-targeted toxin conjugate (Tf-CRM107) for therapy of malignant gliomas”, J Neuro-Oncol 65:3-13, 2003]. Other drugs have also been tested in clinical trials with evidence of some clinical activity. Representative examples include TP-38 [Sampson et al., “Progress report of a phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of a transforming growth factor (TGF)-alpha and a mutated form of the pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors”, J Neuro-Oncol 65:27-35, 2003], and IL4(38-37)-PE38 KDEL [Kawakami et al., “Interleukin-4-pseudomonas exotoxin chimeric fusion protein for malignant glioma therapy”, J Neuro-Oncol 65:15-25, 2003]. The use of IL13-PE38QQR resulted in no definite conclusive statements regarding efficacy [S R Husain and R K Puri, “Interleukin-13 receptor-directed cytotoxin for malignant glioma therapy: from bench to bedside”, J Neuro-Oncol 65:37-48, 2003].
There are many variables affecting the convection, including the catheter size (narrow catheters are more efficient), flow rate (slow flow rates are more efficient), catheter localization [Lidar et al., “Convection-enhanced delivery of paclitaxel for the treatment of recurrent malignant glioma: a Phase I/II clinical study”, Journal of Neurosurgery, 100: 472-479, 2004] and concentration and molecular weight of the infusate [Chen et al., “Variables affecting CED to the striatum: a systematic examination of rate of infusion, cannula size, infusate concentration, and tissue-cannula sealing time”, J Neurosurg 90:315-320, 1999; Chen et al., “Intraparenchymal drug delivery via positive-pressure infusion: experimental and modeling studies of poroelasticity in brain phantom gels”, IEEE Transactions on Biomedical Engineering, 49(2):85-96, 2002]. Additionally, there is significant variability in differential tumor response to the therapeutic drugs, and in the extent of convection among patients and among different types of tissue. For example, convections tends to extend along low resistance paths, such as white matter tracks, necrosis, etc. Convection is also hampered when the treated region reaches regions of liquid accumulation, such as surgery site, sulci, ventricles etc. [Lidar et al., supra].
Moreover, presently known CED techniques are limited by the size of the administered molecule or particle. For molecule, the presently known upper limit is about 200 KDa and for liposomes the upper limit is less than 100 nm [Saito et al., “Distribution of liposomes into brain and rat brain tumor models by convection-enhanced delivery monitored with magnetic resonance imaging”, Cancer Research, 1; 64(7):2572-9, 2004; Mamot et al., “Extensive distribution of liposomes in rodent brains and brain tumors following convection-enhanced delivery”, J Neurooncol 68(1):1-9, 2004].
There is thus a widely recognized need for, and it would be highly advantageous to have a composition for improving efficiency of convection-enhanced drug delivery.